Skip to main content

Advertisement

SpringerLink
Log in

Triglyceride-Rich Lipoproteins, Remnants, and Atherosclerotic Cardiovascular Disease Risk

  • Lipids (M. Shapiro, Section Editor)
  • Published:
Current Cardiovascular Risk Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

To describe seminal studies and recent reports that have focused on the metabolism and quantification of triglyceride-rich lipoproteins (TRL) and remnants. Their role in atherosclerosis pathophysiology and association with cardiovascular risk along with therapeutic approaches is also discussed.

Recent Findings

TRL and remnants are produced by the metabolism of liver-derived very low-density lipoproteins and intestine-derived chylomicrons. They play an important role in atherosclerosis initiation and progression that is independent of low-density lipoprotein particles. Individuals with hypertriglyceridemia have elevated TRL concentration, but direct quantification is challenging. Large-scale epidemiologic studies have demonstrated the independent association of triglycerides, TRL, and remnants with cardiovascular risk. Fibrates and omega-3 fatty acids are commonly used to lower triglycerides and TRL in clinical practice. Volanesorsen is a novel antisense oligonucleotide that lowers triglycerides and TRL by targeting apolipoprotein C-III that has shown promising results in early-stage clinical testing.

Summary

TRL and remnants have an independent and likely causal relationship with atherosclerotic cardiovascular disease. Widespread quantification in clinical practice remains challenging, but emerging targeted therapies herald an exciting future for cardiovascular disease prevention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Castillo-Núñez Y, Morales-Villegas E, Aguilar-Salinas CA. Triglyceride-rich lipoproteins: their role in atherosclerosis. Rev Investig Clínica. 2022;74:61–70.

    Google Scholar 

  2. • Mehta A, Shapiro MD. Apolipoproteins in vascular biology and atherosclerotic disease. Nat Rev Cardiol. 2022;19:168–79. (Comprehensive review focusing on the metabolism of TRL, remnants, and other apolipoproteins and their role in atherosclerosis)

    Article  CAS  PubMed  Google Scholar 

  3. •• Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J. 2021;42:4791–806. (Recent consensus statement from the European Atherosclerosis Society that discusses all aspects of TRL and remnant biology, pathophysiology, clinical measurement, and therapies)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547–63.

    Article  CAS  PubMed  Google Scholar 

  5. Johansen CT, Kathiresan S, Hegele RA. Genetic determinants of plasma triglycerides. J Lipid Res. 2011;52:189–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41:2313–30.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein. Arterioscler Thromb Vasc Biol. 2003;23:160–7.

    Article  CAS  PubMed  Google Scholar 

  8. Hussain A, Ballantyne CM, Saeed A, Virani SS. Triglycerides and ASCVD risk reduction: recent insights and future directions. Curr Atheroscler Rep. 2020. https://doi.org/10.1007/s11883-020-00846-8.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Farnier M, Zeller M, Masson D, Cottin Y. Triglycerides and risk of atherosclerotic cardiovascular disease: an update. Arch Cardiovasc Dis. 2021;114:132–9.

    Article  PubMed  Google Scholar 

  10. Salinas CAA, Chapman MJ. Remnant lipoproteins: are they equal to or more atherogenic than LDL? Curr Opin Lipidol. 2020;31:132–9.

    Article  CAS  PubMed  Google Scholar 

  11. Doi H, Kugiyama K, Oka H, Sugiyama S, Ogata N, Koide SI, Nakamura SI, Yasue H. Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism. Circulation. 2000;102:670–6.

    Article  CAS  PubMed  Google Scholar 

  12. Wang YI, Bettaieb A, Sun C, DeVerse JS, Radecke CE, Mathew S, Edwards CM, Haj FG, Passerini AG, Simon SI. Triglyceride-rich lipoprotein modulates endothelial vascular cell adhesion molecule (VCAM)-1 expression via differential regulation of endoplasmic reticulum stress. PLoS ONE. 2013;8:1–13.

    Google Scholar 

  13. Hadi HAR, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1:183–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Sun C, Alkhoury K, Wang YI, et al. IRF-1 and miRNA126 modulate VCAM-1 expression in response to a high-fat meal. Circ Res. 2012;111:1054–64.

    Article  CAS  PubMed  Google Scholar 

  15. Toth PP. Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease. Vasc Health Risk Manag. 2016;12:171–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Varbo A, Benn M, Tybjærg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation. 2013;128:1298–309.

    Article  CAS  PubMed  Google Scholar 

  17. Reiner Ž. Hypertriglyceridaemia and risk of coronary artery disease. Nat Rev Cardiol. 2017;14:401–11.

    Article  CAS  PubMed  Google Scholar 

  18. Tada H, Nohara A, Kawashiri MA. Serum triglycerides and atherosclerotic cardiovascular disease: insights from clinical and genetic studies. Nutrients. 2018. https://doi.org/10.3390/nu10111789.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Nordestgaard BG, Benn M, Schnohr P, Tybjærg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. J Am Med Assoc. 2007;298:299–308.

    Article  CAS  Google Scholar 

  20. Borén J, Matikainen N, Adiels M, Taskinen MR. Postprandial hypertriglyceridemia as a coronary risk factor. Clin Chim Acta. 2014;431:131–42.

    Article  PubMed  Google Scholar 

  21. Sandesara PB, Virani SS, Fazio S, Shapiro MD. The forgotten lipids: triglycerides, remnant cholesterol, and atherosclerotic cardiovascular disease risk. Endocr Rev. 2019;40:537–57.

    Article  PubMed  Google Scholar 

  22. Teramoto R, Tada H, Kawashiri MA, Nohara A, Nakahashi T, Konno T, Inazu A, Mabuchi H, Yamagishi M, Hayashi K. Molecular and functional characterization of familial chylomicronemia syndrome. Atherosclerosis. 2018;269:272–8.

    Article  CAS  PubMed  Google Scholar 

  23. Nordestgaard BG, Langsted A, Mora S, et al. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points - a joint consensus statement from the European Atherosclerosis Society and European Fede. Eur Heart J. 2016;37:1944–58.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Nordestgaard BG. A test in context: lipid profile, fasting versus nonfasting. J Am Coll Cardiol. 2017;70:1637–46.

    Article  PubMed  Google Scholar 

  25. Martin SS, Blaha MJ, Elshazly MB, Toth PP, Kwiterovich PO, Blumenthal RS, Jones SR. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA - J Am Med Assoc. 2013;310:2061–8.

    Article  CAS  Google Scholar 

  26. •• Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J. 2020;41:99–109. (Recent review focusing on studies that have evaluated the association of triglycerides with cardiovascular disease risk)

    Article  CAS  PubMed  Google Scholar 

  27. Borén J, Packard CJ. Keeping remnants in perspective. Eur Heart J. 2021;42:4333–5.

    Article  PubMed  Google Scholar 

  28. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.

  29. Duran EK, Pradhan AD. Triglyceride-rich lipoprotein remnants and cardiovascular disease. Clin Chem. 2021;67:183–96.

    Article  PubMed  Google Scholar 

  30. Chait A, Ginsberg HN, Vaisar T, Heinecke JW, Goldberg IJ, Bornfeldt KE. Remnants of the triglyceride-rich lipoproteins, diabetes, and cardiovascular disease. Diabetes. 2020;69:508–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hoogeveen RC, Ballantyne CM. Residual cardiovascular risk at low LDL: remnants, lipoprotein(a), and inflammation. Clin Chem. 2021;67:143–53.

    Article  PubMed  Google Scholar 

  32. Joshi PH, Toth PP, Lirette ST, et al. Association of high-density lipoprotein subclasses and incident coronary heart disease: the Jackson Heart and Framingham Offspring Cohort Studies. Eur J Prev Cardiol. 2016;23:41–9.

    Article  PubMed  Google Scholar 

  33. Margraf RL, Calderon FRO, Mao R, Wittwer CT. RET mutation scanning update: Exon 15. Clin Chem. 2009;55:2059–61.

    Article  CAS  PubMed  Google Scholar 

  34. Otvos J. Measurement of triglyceride-rich lipoproteins by nuclear magnetic resonance spectroscopy. Clin Cardiol. 1999. https://doi.org/10.1002/clc.4960221405.

    Article  PubMed  Google Scholar 

  35. Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, Ference BA. Apolipoprotein B particles and cardiovascular disease: a narrative review. JAMA Cardiol. 2019;4:1287–95.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Faridi KF, Quispe R, Martin SS, et al. Comparing different assessments of remnant lipoprotein cholesterol: the very large database of lipids. J Clin Lipidol. 2019;13:634–44.

    Article  PubMed  Google Scholar 

  37. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, De Ferranti S, Faiella-Tommasino J, Forman DE, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Circulation. 2019;139:e1082–143. https://doi.org/10.1161/CIR.0000000000000625.

  38. Scherer J, Singh V, Pitchumoni CS, Yadav D. Issues in hypertriglyceridemic pancreatitis - an update. J Clin Gastroenterol. 2014;48:195–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Haas ME, Attie AD, Biddinger SB. The regulation of ApoB metabolism by insulin. Trends Endocrinol Metab TEM. 2013;24:391–7.

    Article  CAS  PubMed  Google Scholar 

  40. Lampidonis AD, Rogdakis E, Voutsinas GE, Stravopodis DJ. The resurgence of hormone-sensitive lipase (HSL) in mammalian lipolysis. Gene. 2011;477:1–11.

    Article  CAS  PubMed  Google Scholar 

  41. Ginsberg HN. Insulin resistance and cardiovascular disease. J Clin Invest. 2000;106:453–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Klop B, do Rego AT, Cabezas MC. Alcohol and plasma triglycerides. Curr Opin Lipidol. 2013;24:321–6.

    Article  CAS  PubMed  Google Scholar 

  43. Ferrara LA, Marotta T, Rubba P, De Simone B, Leccia G, Soro S, Mancini M. Effects of alpha-adrenergic and beta-adrenergic receptor blockade on lipid metabolism. Am J Med. 1986;80:104–8.

    Article  CAS  PubMed  Google Scholar 

  44. Middeke M, Weisweiler P, Schwandt P, Holzgreve H. Serum lipoproteins during antihypertensive therapy with beta blockers and diuretics: a controlled long-term comparative trial. Clin Cardiol. 1987;10:94–8.

    Article  CAS  PubMed  Google Scholar 

  45. Lasser NL, Grandits G, Caggiula AW, Cutler JA, Grimm RH, Kuller LH, Sherwin RW, Stamler J. Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am J Med. 1984;76:52–66.

    Article  CAS  PubMed  Google Scholar 

  46. Meyer JM. Novel antipsychotics and severe hyperlipidemia. J Clin Psychopharmacol. 2001;21:369–74.

    Article  CAS  PubMed  Google Scholar 

  47. Oray M, Abu Samra K, Ebrahimiadib N, Meese H, Foster CS. Long-term side effects of glucocorticoids. Expert Opin Drug Saf. 2016;15:457–65.

    Article  CAS  PubMed  Google Scholar 

  48. Barrett-Connor E, Wingard D, Criqui M. Postmenopausal estrogen use and heart disease risk factors in the 1980s. Rancho Bernardo, Calif, revisited. JAMA. 1980. https://doi.org/10.1001/JAMA.1989.03420140097034.

    Article  PubMed  Google Scholar 

  49. Castro MR, Nguyen TT, O’Brien T. Clomiphene-induced severe hypertriglyceridemia and pancreatitis. Mayo Clin Proc. 1999;74:1125–8.

    Article  CAS  PubMed  Google Scholar 

  50. Zane LT, Leyden WA, Marqueling AL, Manos MM. A population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. Arch Dermatol. 2006;142:1016–22.

    Article  CAS  PubMed  Google Scholar 

  51. Mateu J, Barrachina F. Hypertriglyceridaemia associated with propofol sedation in critically ill patients. Intensive Care Med. 1996;22:834–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Purnell JQ, Zambon A, Knopp RH, Pizzuti DJ, Achari R, Leonard JM, Locke C, Brunzell JD. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS Lond Engl. 2000;14:51–7.

    Article  CAS  Google Scholar 

  53. Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2:655–66.

    Article  CAS  PubMed  Google Scholar 

  54. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111–88.

    Article  PubMed  Google Scholar 

  55. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996;3:213–9.

    Article  CAS  PubMed  Google Scholar 

  56. Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, Boekholdt SM, Khaw K-T, Gudnason V. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115:450–8.

    Article  CAS  PubMed  Google Scholar 

  57. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299–308.

    Article  CAS  PubMed  Google Scholar 

  58. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;298:309–16.

    Article  CAS  PubMed  Google Scholar 

  59. Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA. 2008;300:2142–52.

    Article  CAS  PubMed  Google Scholar 

  60. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease. Circ Res. 2016;118:547–63.

    Article  CAS  PubMed  Google Scholar 

  61. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet Lond Engl. 2014;384:626–35.

    Article  CAS  Google Scholar 

  62. Varbo A, Nordestgaard BG. Nonfasting triglycerides, low-density lipoprotein cholesterol, and heart failure risk: two cohort studies of 113 554 Individuals. Arterioscler Thromb Vasc Biol. 2018;38:464–72.

    Article  CAS  PubMed  Google Scholar 

  63. Collaboration ERF, Di Angelantonio E, Sarwar N, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–2000.

    Article  Google Scholar 

  64. Lawler PR, Kotrri G, Koh M, Goodman SG, Farkouh ME, Lee DS, Austin PC, Udell JA, Ko DT. Real-world risk of cardiovascular outcomes associated with hypertriglyceridaemia among individuals with atherosclerotic cardiovascular disease and potential eligibility for emerging therapies. Eur Heart J. 2020;41:86–94.

    Article  PubMed  Google Scholar 

  65. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:427–36.

    Article  CAS  PubMed  Google Scholar 

  66. Varbo A, Freiberg JJ, Nordestgaard BG. Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population. Clin Chem. 2015;61:533–43.

    Article  CAS  PubMed  Google Scholar 

  67. Saeed A, Feofanova EV, Yu B, et al. Remnant-like particle cholesterol, low-density lipoprotein triglycerides, and incident cardiovascular disease. J Am Coll Cardiol. 2018;72:156–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Silbernagel G, Scharnagl H, Kleber ME, et al. LDL triglycerides, hepatic lipase activity, and coronary artery disease: an epidemiologic and Mendelian randomization study. Atherosclerosis. 2019;282:37–44.

    Article  CAS  PubMed  Google Scholar 

  69. Hoogeveen RC, Gaubatz JW, Sun W, et al. Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: the Atherosclerosis Risk In Communities (ARIC) study. Arterioscler Thromb Vasc Biol. 2014;34:1069–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Balling M, Nordestgaard BG, Langsted A, Varbo A, Kamstrup PR, Afzal S. Small dense low-density lipoprotein cholesterol predicts atherosclerotic cardiovascular disease in the Copenhagen General Population Study. J Am Coll Cardiol. 2020;75:2873–5.

    Article  CAS  PubMed  Google Scholar 

  71. Duran EK, Aday AW, Cook NR, Buring JE, Ridker PM, Pradhan AD. Triglyceride-rich lipoprotein cholesterol, small dense LDL cholesterol, and incident cardiovascular disease. J Am Coll Cardiol. 2020;75:2122–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ikezaki H, Lim E, Cupples LA, Liu C-T, Asztalos BF, Schaefer EJ. Small dense low-density lipoprotein cholesterol is the most atherogenic lipoprotein parameter in the Prospective Framingham Offspring Study. J Am Heart Assoc. 2021;10:e019140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Thomsen M, Varbo A, Tybjærg-Hansen A, Nordestgaard BG. Low nonfasting triglycerides and reduced all-cause mortality: a mendelian randomization study. Clin Chem. 2014;60:737–46.

    Article  CAS  PubMed  Google Scholar 

  74. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C–lowering LDLR variants with risk of coronary heart disease. JAMA. 2019;321:364–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jørgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG, Tybjærg-Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J. 2013;34:1826–33.

    Article  PubMed  Google Scholar 

  77. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32–41.

    Article  PubMed  Google Scholar 

  78. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, Crosby J, Peloso GM, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371:22–31.

    Article  Google Scholar 

  79. Karlson BW, Palmer MK, Nicholls SJ, Lundman P, Barter PJ. A VOYAGER meta-analysis of the impact of statin therapy on low-density lipoprotein cholesterol and triglyceride levels in patients with hypertriglyceridemia. Am J Cardiol. 2016;117:1444–8.

    Article  CAS  PubMed  Google Scholar 

  80. Fruchart JC. Peroxisome proliferator-activated receptor-alpha activation and high-density lipoprotein metabolism. Am J Cardiol. 2001;88:24N-29N.

    Article  CAS  PubMed  Google Scholar 

  81. Shapiro MD, Fazio S. From lipids to inflammation: new approaches to reducing atherosclerotic risk. Circ Res. 2016;118:732–49.

    Article  CAS  PubMed  Google Scholar 

  82. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–45.

    Article  CAS  PubMed  Google Scholar 

  83. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet Lond Engl. 2005;366:1849–61.

    Article  CAS  Google Scholar 

  84. Bezafibrate Infarction Prevention (BIP) study. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation. 2000;102:21–7.

    Article  Google Scholar 

  85. Elam MB, Ginsberg HN, Lovato LC, et al. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. JAMA Cardiol. 2017;2:370–80.

    Article  PubMed  Google Scholar 

  86. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse JR III, Leiter LA, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74. https://doi.org/10.1056/NEJMoa1001282.

  87. Harris WS, Bulchandani D. Why do omega-3 fatty acids lower serum triglycerides? Curr Opin Lipidol. 2006;17:387–93.

    Article  CAS  PubMed  Google Scholar 

  88. Khan S, Minihane A-M, Talmud PJ, Wright JW, Murphy MC, Williams CM, Griffin BA. Dietary long-chain n-3 PUFAs increase LPL gene expression in adipose tissue of subjects with an atherogenic lipoprotein phenotype. J Lipid Res. 2002;43:979–85.

    Article  CAS  PubMed  Google Scholar 

  89. Park Y, Harris WS. Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J Lipid Res. 2003;44:455–63.

    Article  PubMed  Google Scholar 

  90. Kromhout D, Bosschieter EB, de Lezenne CC. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985;312:1205–9.

    Article  CAS  PubMed  Google Scholar 

  91. Zheng J, Huang T, Yu Y, Hu X, Yang B, Li D. Fish consumption and CHD mortality: an updated meta-analysis of seventeen cohort studies. Public Health Nutr. 2012;15:725–37.

    Article  PubMed  Google Scholar 

  92. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet Lond Engl. 2007;369:1090–8.

    Article  CAS  Google Scholar 

  93. Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis. 2008;200:135–40.

    Article  CAS  PubMed  Google Scholar 

  94. Kromhout D, Giltay EJ, Geleijnse JM, Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363:2015–26.

    Article  CAS  PubMed  Google Scholar 

  95. Trial Investigators ORIGIN, Bosch J, Gerstein HC, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367:309–18.

    Article  Google Scholar 

  96. Manson JE, Cook NR, Lee I-M, et al. Marine n−3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2019;380:23–32.

    Article  CAS  PubMed  Google Scholar 

  97. Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7:CD003177.

    PubMed  Google Scholar 

  98. •• Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11–22. (Large contemporary randomized clinical trial demonstrating cardiovascular risk reduction with purified EPA (icosapent ethyl) in a secondary prevention population)

    Article  CAS  PubMed  Google Scholar 

  99. •• Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH Randomized Clinical Trial. JAMA. 2020;324:2268–80. (Large contemporary randomized clinical trial demonstrating lack of risk reduction with combination EPA and DHA)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Investigators AIM-HIGH, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.

    Article  Google Scholar 

  101. HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–12.

    Article  Google Scholar 

  102. Ginsberg HN, Le NA, Goldberg IJ, Gibson JC, Rubinstein A, Wang-Iverson P, Norum R, Brown WV. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest. 1986;78:1287–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Reyes-Soffer G, Sztalryd C, Horenstein RB, et al. Effects of APOC3 heterozygous deficiency on plasma lipid and lipoprotein metabolism. Arterioscler Thromb Vasc Biol. 2019;39:63–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008;322:1702–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015;373:438–47.

    Article  CAS  PubMed  Google Scholar 

  106. •• Witztum JL, Gaudet D, Freedman SD, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med. 2019;381:531–42. (Phase 2 clinical trial demonstrating efficacy of antisense oligonucleotide volanesorsen that targets ApoC-III to lower triglycerides and triglyceride-rich lipoproteins)

    Article  CAS  PubMed  Google Scholar 

  107. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med. 2017;377:211–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol. 2017;69:2054–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur Heart J. 2020;41:3936–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ahmad Z, Banerjee P, Hamon S, et al. Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia. Circulation. 2019;140:470–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Ueda M, Wolska A, Burke FM, Escobar M, Walters L, Lalic D, Hegele RA, Remaley AT, Rader DJ, Dunbar RL. Experimental therapeutics for challenging clinical care of a patient with an extremely rare homozygous APOC2 mutation. Case Rep Endocrinol. 2020;2020:e1865489.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. All India Institute of Medical Sciences, New Delhi, India

    Vishwesh M. Bharadiya

  2. Division of Biophysics, Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Medical University of Graz, Graz, Austria

    Swasti Rawal

  3. Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA

    Vardhmaan Jain

  4. Section On Hospital Medicine, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Parag A. Chevli

  5. Division of Cardiology, Department of Internal Medicine, VCU Health Pauley Heart Center, Virginia Commonwealth University, 1200 East Broad Street, PO Box 980036, Richmond, VA, 23298, USA

    Anurag Mehta

Authors
  1. Vishwesh M. Bharadiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Swasti Rawal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vardhmaan Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Parag A. Chevli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anurag Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anurag Mehta.

Ethics declarations

Human and Animal Rights

This article does not contain any studies with human or animal subjects performed by any of the authors.

Conflict of Interest

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Lipids

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bharadiya, V.M., Rawal, S., Jain, V. et al. Triglyceride-Rich Lipoproteins, Remnants, and Atherosclerotic Cardiovascular Disease Risk. Curr Cardiovasc Risk Rep 16, 131–144 (2022). https://doi.org/10.1007/s12170-022-00702-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12170-022-00702-1

Keywords

Search

Navigation